This mentored clinical scientist research Career Development Award (KO8) proposal describes the 5-year training program for Dr. Heitham Hassoun. The proposal builds upon the candidate's strengths and prior research skills, and takes advantage of the extensive resources available at The Johns Hopkins University. Through the mentorship of Drs. Hamid Rabb and Rubin Tuder, and a structered didactic program, Dr. Hassoun will be given the tools and training to advance to the level of a fully independent surgeon scientist. The overall objective of this research proposal is to gain an understanding of the pathophysiological kidney-lung interactions during kidney ischemia-reperfusion injury (IRI) with an emphasis on the pulmonary endothelial response under these conditions. Despite advances in renal replacement therapy, acute kidney injury (AKI) continues to be associated with unacceptably high mortality. Recent studies have shown the importance of AKI on dysfunction of extra-renal organs, and with current availability of dialysis, AKIassociated distant organ injury constitutes the major cause of death in these patients. Based on prior clinical and laboratory investigations, we hypothesize that kidney IRI induces T lymphocyte dependent pulmonary endothelial apoptosis that contributes to subsequent acute lung injury (All). Specific aim #1 will characterize the effect of kidney IRI on acute lung injury and inflammation. Using established rodent models of ischemic AKI, we will investigate the in vivo effects of kidney IRI on lung injury and inflammation and the in vitro effects of post-IRI plasma on cultured endothelial barrier function. Specific aim #2 will investigate the role of pulmonary apoptosis in ischemic AKI-induced ALL Specifically, we will determine if pulmonary endothelial apoptosis mediates 1) kidney IRI-induced All in vivo and 2) post- IRI plasma induced barrier dysfunction in vitro, and identify the potential death receptor pathways involved. Specific aim #3 will investigate the potential role of T lymphocyte mediated pathways on kidney IRIinduced pulmonary apoptosis and ALL Using mice deficient in T cells/T cell subsets as well as adoptive transfer techniques, we will determine if T cells mediate pulmonary apoptosis and ALL The findings of the proposed studies will provide insight into the effector mechanisms of kidney-lung interactions during ischemia-reperfusion injury and serve as the basis for further mechanistic studies.